Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist.
Jeremy J Roach, Yusuke Sasano, Cullen L. Schmid, Saheem A. Zaidi, Vsevolod Katritch, Raymond C. Stevens, Laura M Bohn, Ryan A Shenvi
ACS Central Science December 27, 2017 DOI: 10.1021/acscentsci.7b00488 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or methodological paper Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Key points | Proposes that deletion of C20 from salvinorin A stabilizes the skeleton, simplifies synthesis, and retains high affinity and selectivity for the kappa-opioid receptor. |
Abstract
Salvinorin A (SalA) is a plant metabolite that agonizes the human kappa-opioid receptor (κ-OR) with high affinity and high selectivity over mu- and delta-opioid receptors. Its therapeutic potential has stimulated extensive semisynthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been frustrated by its dense, complex architecture. Treatment of strategic bonds in SalA as dynamic and dependent on structural perturbation enabled the identification of an efficient retrosynthetic pathway. Here we show that deletion of C20 simultaneously stabilizes the SalA skeleton, simplifies its synthesis, and retains its high affinity and selectivity for the κ-OR. The resulting 10-step synthesis now opens the SalA scaffold to deep-seated property modification. Finally, we describe a workflow to identify structural changes that retain molecular complexity, but reduce synthetic complexity-two related, but independent ways of looking at complexity.
Comparable studies
Other theoretical and historical papers on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. | 2008 | Theoretical or philosophical paper | |
| The claustrum's proposed role in consciousness is supported by the effect and target localization of Salvia divinorum. | 2014 | Theoretical or philosophical paper | |
| Total Synthesis of (-)-Salvinorin A. | 2016 | Theoretical or philosophical paper | |
| Title: DMT, Salvinorin A, and Stress Regulation: An Exploratory Neuropharmacological Research Proposal | 2026 | Theoretical or philosophical paper | |
| Salvia Divinorum: entrSalvia divinorum: Entre la prohibición y la construcción de su conocimientoe a proibição e a construção do seu saber | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 12
- Natural Product Synthesis in the 21st Century: Beyond the Mountain Top ACS Central Science February 14, 2024
- DARK Classics in Chemical Neuroscience: Salvinorin A. ACS Chemical Neuroscience December 2, 2020
- Total Synthesis of the Neoclerodane Diterpene Salvinorin A via an Intramolecular Diels–Alder Strategy Organic Letters May 22, 2018
- Salvaging Salvinorin: From Hallucinogen to Potential Therapeutic through Chemical Synthesis ACS Central Science August 10, 2023
- Chemical syntheses of the salvinorin chemotype of KOR agonist. Natural Product Reports November 18, 2020
and 7 more in the library
Cites 9
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. Organic Letters April 3, 2008
- Total Synthesis of (-)-Salvinorin A. Chemistry - A European Journal December 12, 2016
- Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A. Journal of Natural Products April 25, 2011
and 4 more in the library